Intraoperative lymphatic mapping to localize sentinel lymph nodes (SLNs) and stage breast cancer patients is currently performed after administration of radioisotopes and / or dye. However, each of these methods has potential limitations that can impact the detection of SLNs and the accuracy of disease staging. Furthermore, isotope imaging requires ionizing radiation, blue dye can cause anaphylactic reactions and neither of these techniques provides an accurate noninvasive depiction of lymphatic anatomy. Up to 25% of patients experience complications such as lymphedema. Our group has demonstrated that contrast-enhanced ultrasound imaging (CEUS) after subdermal administration of a tissue-specific ultrasound contrast agent, can be used to noninvasively map lymphatic drainage and localize SLNs (so called lymphosonography). Our NIH funded investigations using a swine model with naturally occurring melanomas have confirmed that CEUS is superior to radioisotope imaging detection almost 20 % more SLNs. The fundamental hypothesis of this project is that CEUS can be used to map lymphatic drainage from breast malignancies and localize SLNs in breast cancer patients and that lymphosonography will improve the detection of SLNs compared to isotope mapping leading to improved disease staging. Initially, a dose-finding study will be performed in 12 healthy female volunteers to determine the optimal dose as well as the safety and tolerability of the tissue-specific, contrast agent Sonazoid (GE Healthcare, Oslo, Norway) for human lymphatic applications. Then a clinical trial of lymphosonography will compare SLN identification to that of isotope mapping during surgery of 90 breast cancer patients. A state-of- the-art ultrasound scanner with contrast-specific imaging capabilities will be used to localize lymphatic drainage from breast cancers after subdermal administration of Sonazoid. The number and locations of the SLNs identified by the two imaging modalities (CEUS and isotope mapping) will be compared using McNemar's test for correlated proportions as well as using a one-sided t-test with a Wilcoxon non-parametric adjustment (assuming a normal distribution) with dye-guided surgery as the reference standard for SLN detection. In summary, this study aims to determine the clinical potential of lymphosonography for noninvasive SLN mapping in 90 breast cancer patients and compare the use of CEUS to isotope mapping.